There are high unmet medical needs in the few established therapies for several autoimmune, inflammatory and metabolic diseases. Despite the diverse clinical manifestations of these diseases, Retinoic Acid Receptor-Related Orphan Receptors (RORs) regulate and contribute to the pathogenesis of these diseases through modulation of immune responses and lipid/glucose homeostasis. Only recently has the critical regulatory role of RORs been well-characterized and target validated in several animal models of some of these diseases.
RORs are transcription factors which belong to the nuclear hormone receptor superfamily (Jetten (2009) Nucl. Recept. Signal., 7:e003; Jetten et al. (2013) Front Endocrinol. (Lausanne), 4:1; Jetten & Joo (2006) Adv. Dev. Biol., 16:313-355). The ROR subfamily consists of three major isoforms: RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3), encoded by the RORA, RORB and RORC genes, respectively. RORs are multidomain proteins that contain four principal domains typical of nuclear receptors: a highly variable N-terminal A/B domain, a highly conserved DNA-binding domain (DBD), a ligand binding domain (LBD) that contains the ligand-dependent activation function-2 (AF-2), and a hinge domain between the DBD and LBD. Each ROR gene through alternative splicing and promoter usage generates several ROR isoforms that differ only in their amino-terminus.
In humans, there are four RORα isoforms (RORα1-4), one RORβ1 isoform, and two RORγ isoforms (RORγ1 and RORγ2 [RORγt]) that are expressed in a highly tissue-specific manner. RORα and RORγ play an important role in the regulation of lipid/glucose homeostasis, cellular metabolism, immune function and circadian rhythms, and have been implicated in the pathogenesis of several autoimmune, inflammatory and metabolic diseases (Burris et al. (2012) Chem. Biol., 19:51-59; Burris et al. (2013) Pharmacol. Rev., 65:710-778; Huh & Littman (2012) Eur. J. Immunol., 42:2232-2237; Jetten (2009) Nucl. Recept. Signal., 7:e003; Jetten, Kang, and Takeda 2013 Front Endocrinol. (Lausanne), 4:1). Synthetic ligands have been described that interact with the RORα and RORγ LBD functioning as a switch that induces a ROR LBD conformational change. Such change promotes the recruitment and displacement of regulatory coactivator and corepressor proteins and upon ROR DBD binding to the ROR responsive element of the target genes lead to the induction or inhibition of ROR-regulated gene transcriptional activity. Therefore, small molecule drugs that bind to the nuclear receptor LBDs such as ROR could elicit a variety of pharmacological responses, including activation (agonists), inactivation (antagonists or non-agonists), and for receptors that are constitutively active, ligands can downregulate the constitutive response (inverse agonists).
RORγt is the master regulator of human T Helper 17 (TH17) cell differentiation, function and cytokine production (Ivanov et al. (2006) Cell, 126:1121-1133). The critical role of TH17 cells in the pathogenesis of autoimmune and inflammatory diseases has been established and is conferred by the production of its signature proinflammatory cytokines IL-17A, IL-17F, IL-17AF, IL-21, IL-22 (Ghoreschi et al. (2010) Nature, 467:967-971; Lee et al. (2012) Nat. Immunol., 13:991-999; Miossec et al. (2009) N. Engl. J. Med., 361:888-898; Miossec & Kolls (2012) Nat. Rev. Drug Discov., 11:763-776; Zepp et al. (2011) Trends Immunol., 32:232-239). Although several transcription factors regulate TH17, γ/δ T and innate lymphoid cells as important sources of TH17 cytokines, these cells are distinguished by its specific regulation of RORγt for cytokine transcriptional output and effector functions and to a lesser extent by RORα in humans (Cua & Tato (2010) Nat. Rev. Immunol., 10:479-489; Huh & Littman 2012 Eur. J. Immunol., 42:2232-2237; Ivanov et al. (2006) Cell, 126:1121-1133; Spits & Di Santo (2011) Nat. Immunol., 12:21-27; Sutton et al. (2012) Eur. J. Immunol., 42:2221-2231). Also, in several autoimmune disease models, there is a relative imbalance of increased TH17 cells over low numbers of immunosuppressive CD4+CD25+Foxp3+ regulatory T cells [TReg] (Edwards et al. (2011) J. Neurol., 258:1518-1527; Littman & Rudensky (2010) Cell, 140:845-858). Targeting RORγt could have a broader anti-inflammatory effect on the combined inhibition of all TH17 cytokine production and inflammatory cellular function, and in the induction and expansion of suppressive TReg cells, important in autoimmune and inflammatory disease resolution, and may also have therapeutic potential in metabolic diseases such as diet-induced insulin resistance known to be regulated by RORγ.
Since both RORγ1 and RORγt [RORγ1] protein isoforms, contain identical LBDs, small molecule RORγ modulators that inhibit RORγt activity will also inhibit RORγ. RORα similarly plays an important regulatory role in the pathogenesis of autoimmune and inflammatory disorders, and also in metabolic diseases.
RORα critically regulates lipid and glucose homeostasis and cellular metabolism that contribute to the development of metabolic diseases. The therapeutic benefits of inhibiting RORα for metabolic diseases is associated with diminished inflammation and downregulated expression of RORα target genes as seen in RORα-deficient mice. As ligand-dependent transcription factors, it is desirable to prepare compounds that modulate RORα and/or RORγ activity which can be used in the treatment of RORα- and/or RORγ-regulated autoimmune, inflammatory and metabolic diseases.